Acquired nephrogenic diabetes insipidus (acquired NDI) is a common debilitating and morbid condition in the clinic due to a variety of causes. The salient feature of all forms of acquired NDI is resistance of the kidney to the action of the anti-diuretic hormone (ADH or arginine vasopressin, AVP), and so it is often associated with increased blood ADH levels. Acquired NDI is characterized by polydipsia (increased water intake), polyuria (increased urine output) and impaired concentrating ability of the kidney (decreased urine osmolality), associated with marked decrease in ADH-regulated AQP2 water channel in the kidney medulla. This is due to the resistance of the kidney to the action of the anti-diuretic hormone (ADH or AVP). Vasopressin (AVP or ADH), acting through its V2 receptor in the collecting duct principal cells of the kidney, and the associated cAMP signaling pathway and aquaporin (AQP) water channels, plays a central role in water homeostasis (for reviews see Schrier, R. W. (2007) Curr Opin Investig Drugs. 8:304-11; Boone M. and Deen, P. M. (2008) Pflugers Arch. 456:1005-24). However, a variety of autocrine and paracrine agents, acting through their respective membrane receptors in the collecting duct have been shown to modulate the action of AVP.
Acquired NDI is a common condition in the clinic with significant degree of morbidity, or even mortality if not treated properly. Apart from social inconvenience, NDI is a debilitating condition, with an elevated risk of dehydration, hypernatremia, altered consciousness, and hemodynamic instability from hypovolemia, especially in elderly patients. The most common causes of acquired NDI are lithium-induced or hypokalemic or hypercalcemic nephropathy or post-obstructive uropathy.
Currently used therapies for acquired NDI, such as administration of cyclooxygenase (COX) inhibitors or thiazides or amiloride, are associated with varying degrees of success as well as adverse effects, especially in critically ill and elderly patients. Hence, there is a need to introduce newer therapies with fewer side effects and better tolerability in all patients.
Despite advances in the treatment of renal disease and disorders, there is still a scarcity of compounds that are effective in the treatment of acquired NDI. These needs and other needs are satisfied by the present invention.